US6403813B1 - Method for the preparation of 5-carboxyphthalide - Google Patents

Method for the preparation of 5-carboxyphthalide Download PDF

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Publication number
US6403813B1
US6403813B1 US09/692,653 US69265300A US6403813B1 US 6403813 B1 US6403813 B1 US 6403813B1 US 69265300 A US69265300 A US 69265300A US 6403813 B1 US6403813 B1 US 6403813B1
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Prior art keywords
carboxyphthalide
terephthalic acid
oleum
water
reaction
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Expired - Fee Related
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US09/692,653
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English (en)
Inventor
Hans Petersen
Poul Dahlberg Nielsen
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H Lundbeck AS
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H Lundbeck AS
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US case filed in New York Southern District Court litigation https://portal.unifiedpatents.com/litigation/New%20York%20Southern%20District%20Court/case/1%3A06-cv-02869 Source: District Court Jurisdiction: New York Southern District Court "Unified Patents Litigation Data" by Unified Patents is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by H Lundbeck AS filed Critical H Lundbeck AS
Assigned to H. LUNDBECK A/S reassignment H. LUNDBECK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NIELSEN, POUL DAHLBERG, PETERSEN, HANS
Priority to US10/140,361 priority Critical patent/US6888009B2/en
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Publication of US6403813B1 publication Critical patent/US6403813B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the present invention relates to a novel process for the preparation of 5-carboxyphthalide, a starting material for the manufacture of the well-known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
  • Citalopram is a selective serotonin reuptake inhibitor which has successfully been marketed as an antidepressant drug for some years, It has the following structure:
  • the 5-cyanophthalide may in its turn be obtained by reaction of 5-carboxyphthalide with a dehydrating agent and a sulfonamide of the formula H 2 N-SO 2 -R wherein R is NH 2 , alkyloxy, optionally substituted phenyloxy, or substituted phenyl in order to obtain 5-cyanophthalide, cf. our co-pending Danish patent application No. PA199801718.
  • 5-Carboxyphthalide has been described as a useful intermediate in the polymer and paint industry. However, no reliable commercial source is available at present.
  • a known process comprises catalytic hydrogenation of trimellithic acid (DE-A1 2630927). This process provides a mixture of the 5- and 6-carboxyphthalides and, accordingly, it requires elaborate and costly purification.
  • 5-carboxyphthalide is synthesised by reaction of terephthalic acid with trioxane in liquid SO 3 . During this process, trioxane sublimates and precipitates thereby obstructing the equipment.
  • 5-carboxyphthalide may be prepared from terephthalic acid in high yields by a convenient, cost-effective procedure.
  • the present invention provides a process for the manufacture of 5-carboxyphthalide
  • the oleum used is commercially available oleum. So the following are available from Aldrich/Fluka:
  • the terephthalic acid is condensed with paraformaldehyde liberating water, which reacts with the SO 2 .
  • 5-carboxyphthalide may be isolated as follows: The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase. The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, filtered off, washed with water and dried.
  • 1.0-1.33 equivalents CH 2 O and 1.0-2.5, preferably 1.0-2.0 are used. More preferably 1.25-1.5 equivalents SO 3 per equivalent terephthalic acid are used. Most preferably, about 1.37 equivalents (corresponding to about 3.3 kg 20-25% oleum/kg terephthalic acid) are used per equivalent terephthalic acid.
  • the reaction of terephthalic acid with paraformaldehyde is carried out at elevated temperature, conveniently at about 50-148° C., preferably 115-125° C. or 138-148° C.
  • the reaction time is not critical and may easily be determined by a person skilled in the art, a reaction time of 17-21 hours is preferably used for a 210 kg batch at 115-125° C. The time is decreased with increasing temperature.
  • the adjustment of pH to 6.3 to 7.3 in order to dissolve the 5-carboxyphthalide formed may be effected by NaOH, e.g. about 10% aqueous NaOH.
  • the terephthalic acid used as a starting material is commercially available.
  • the invention is further illustrated by the following example.
  • Terephthalic acid (10 kg) is charged into a reactor. Oleum (20% (18-24% SO 3 ); 6 kg/kg terephthalic acid ) is added and then paraformaldehyde (1.33 equivalents, 0.24 kg/kg terephthalic acid) is added. The mixture is agitated at 125° C. for 17 hours. Water (13 kg/kg terephthalic acid and filter aid is added, the temperature is adjusted to about 70° C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH, activated carbon, 0.07 kg/kg terephthalic acid is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 65° C. and the pH is adjusted to about 2 with 50% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 83%.
  • Oleum (20-25% SO 3 43 kg) is charged into a reactor.
  • Terephthalic acid (13 Kg) and then paraformaldehyde (3.8 Kg) is added.
  • the mixture is agitated at 138-148° C. for 41 ⁇ 2 hours.
  • Water (87 L) is added and the temperature is adjusted to about 100° C.
  • the precipitate is filtered of, washed with water and suspended in water.
  • the pH of the suspension is adjusted to about 7 with NaOH (about 10%), activated carbon, 0.5 Kg is added, and then the mixture is filtered, the precipitate is rinsed with water.
  • the temperature of the filtrate is adjusted to about 85° C. and the pH is adjusted to about 2 with 96% sulfuric acid.
  • the 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 82%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Indole Compounds (AREA)
  • Seasonings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US09/692,653 1999-11-01 2000-10-19 Method for the preparation of 5-carboxyphthalide Expired - Fee Related US6403813B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/140,361 US6888009B2 (en) 1999-11-01 2002-05-06 Method for the preparation of 5-carboxyphthalide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA199901569 1999-11-01
DK01569/99 1999-11-01

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/140,361 Division US6888009B2 (en) 1999-11-01 2002-05-06 Method for the preparation of 5-carboxyphthalide

Publications (1)

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US6403813B1 true US6403813B1 (en) 2002-06-11

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US09/692,653 Expired - Fee Related US6403813B1 (en) 1999-11-01 2000-10-19 Method for the preparation of 5-carboxyphthalide
US10/140,361 Expired - Fee Related US6888009B2 (en) 1999-11-01 2002-05-06 Method for the preparation of 5-carboxyphthalide

Family Applications After (1)

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US10/140,361 Expired - Fee Related US6888009B2 (en) 1999-11-01 2002-05-06 Method for the preparation of 5-carboxyphthalide

Country Status (13)

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US (2) US6403813B1 (de)
EP (1) EP1235819A1 (de)
JP (1) JP2003513084A (de)
CN (1) CN1187348C (de)
AR (1) AR026063A1 (de)
AU (1) AU7902400A (de)
BR (1) BR0015471A (de)
CA (1) CA2389379C (de)
HK (1) HK1052702A1 (de)
HR (1) HRP20020405A2 (de)
IT (1) IT1319251B1 (de)
MX (1) MXPA02004313A (de)
WO (1) WO2001032642A1 (de)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1118614A2 (de) † 2000-01-18 2001-07-25 Norpharma SpA Verfahren zur Herstellung von 5-Carboxyphthalid
US20020165403A1 (en) * 1999-11-01 2002-11-07 H. Lundbeck A/S Method for the preparation of 5-carboxyphthalide
US20030013895A1 (en) * 2000-01-14 2003-01-16 H. Lundbeck A/S Method for the preparation of 5-cyanophthalide
US20030060640A1 (en) * 2000-03-16 2003-03-27 H. Lundbeck A/S Method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans
US20030083509A1 (en) * 2000-03-13 2003-05-01 H. Lundbeck A/S Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofurans
US6660873B2 (en) 2000-05-12 2003-12-09 H. Lundbeck A/S Method for the preparation of citalopram
US6717000B2 (en) 2000-03-13 2004-04-06 H. Lundbeck A/S Method for the preparation of citalopram
US6762308B2 (en) 2000-03-13 2004-07-13 H. Lundbeck A/S Method for the preparation of citalopram
US6762307B2 (en) 1999-12-28 2004-07-13 H. Lundbeck A/S Method for the preparation of citalopram
US6768011B2 (en) 2000-03-03 2004-07-27 H. Lundbeck A/S Method for the preparation of citalopram
US6806376B2 (en) 2000-03-14 2004-10-19 H. Lundbeck A.S Method for the preparation of citalopram
US6849749B2 (en) 1999-04-14 2005-02-01 H. Lundbeck A/S Method for the preparation of citalopram
US7271273B2 (en) 1999-12-30 2007-09-18 H. Lundbeck A/S Method for the preparation of citalopram
US20080058536A1 (en) * 2003-03-21 2008-03-06 H. Lundbeck A/S Intermediates for the preparation of citalopram and escitalopram
US20090088469A1 (en) * 1999-06-25 2009-04-02 H. Lundbeck A/S Method for the preparation of citalopram
CN112062741A (zh) * 2019-06-11 2020-12-11 太仓市茜泾化工有限公司 一种5-羧酸苯酞的制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0005477D0 (en) 2000-03-07 2000-04-26 Resolution Chemicals Limited Process for the preparation of citalopram
US20050154052A1 (en) * 2003-03-24 2005-07-14 Hetero Drugs Limited Novel crystalline forms of (s)-citalopram oxalate
WO2006090409A1 (en) * 2005-02-28 2006-08-31 Kekule Pharma Ltd., An improved process for the preparation of 5 - carboxyphthalide
CN106632183A (zh) * 2016-12-07 2017-05-10 万全万特制药（厦门）有限公司 一种草酸艾司西酞普兰杂质的制备方法

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US3467675A (en) 1965-03-18 1969-09-16 Kefalas As Antidepressant basic derivatives of phthalanes,iso-chromanes and iso-chromenes
US4136193A (en) 1976-01-14 1979-01-23 Kefalas A/S Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans
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US6020501A (en) * 1996-07-10 2000-02-01 Basf Aktiengesellschaft Process for preparing phthalides
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050124817A1 (en) * 1999-04-14 2005-06-09 Hans Petersen Method for the preparation of citalopram
US6849749B2 (en) 1999-04-14 2005-02-01 H. Lundbeck A/S Method for the preparation of citalopram
US7030252B2 (en) 1999-04-14 2006-04-18 H. Lundbeck A/S Method for the preparation of citalopram
US20090088469A1 (en) * 1999-06-25 2009-04-02 H. Lundbeck A/S Method for the preparation of citalopram
US20020165403A1 (en) * 1999-11-01 2002-11-07 H. Lundbeck A/S Method for the preparation of 5-carboxyphthalide
US6888009B2 (en) * 1999-11-01 2005-05-03 H. Lundbeck A/S Method for the preparation of 5-carboxyphthalide
US6762307B2 (en) 1999-12-28 2004-07-13 H. Lundbeck A/S Method for the preparation of citalopram
US7271273B2 (en) 1999-12-30 2007-09-18 H. Lundbeck A/S Method for the preparation of citalopram
US20030013895A1 (en) * 2000-01-14 2003-01-16 H. Lundbeck A/S Method for the preparation of 5-cyanophthalide
US6911548B2 (en) 2000-01-14 2005-06-28 H. Lundbeck A/S Method for the preparation of 5-cyanophthalide
EP1118614B2 (de) † 2000-01-18 2011-03-09 Infosint Sa Verfahren zur Herstellung von 5-Carboxyphthalid
EP1118614A2 (de) † 2000-01-18 2001-07-25 Norpharma SpA Verfahren zur Herstellung von 5-Carboxyphthalid
US6768011B2 (en) 2000-03-03 2004-07-27 H. Lundbeck A/S Method for the preparation of citalopram
US20050020670A1 (en) * 2000-03-13 2005-01-27 H. Lundbeck A/S Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran
US6864379B2 (en) 2000-03-13 2005-03-08 H. Lundbeck A/S Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofurans
US20040215025A1 (en) * 2000-03-13 2004-10-28 H. Lundbeck A/S Method for the preparation of citalopram
US6762308B2 (en) 2000-03-13 2004-07-13 H. Lundbeck A/S Method for the preparation of citalopram
US6992198B2 (en) 2000-03-13 2006-01-31 H. Lundbeck A/S Method for the preparation of citalopram
US6717000B2 (en) 2000-03-13 2004-04-06 H. Lundbeck A/S Method for the preparation of citalopram
US20030083509A1 (en) * 2000-03-13 2003-05-01 H. Lundbeck A/S Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofurans
US6806376B2 (en) 2000-03-14 2004-10-19 H. Lundbeck A.S Method for the preparation of citalopram
US20030060640A1 (en) * 2000-03-16 2003-03-27 H. Lundbeck A/S Method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans
US6660873B2 (en) 2000-05-12 2003-12-09 H. Lundbeck A/S Method for the preparation of citalopram
US20080058536A1 (en) * 2003-03-21 2008-03-06 H. Lundbeck A/S Intermediates for the preparation of citalopram and escitalopram
US7687645B2 (en) * 2003-03-21 2010-03-30 H. Lundbeck A/S Intermediates for the preparation of citalopram and escitalopram
CN112062741A (zh) * 2019-06-11 2020-12-11 太仓市茜泾化工有限公司 一种5-羧酸苯酞的制备方法

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EP1235819A1 (de) 2002-09-04
BR0015471A (pt) 2002-07-09
HK1052702A1 (en) 2003-09-26
HRP20020405A2 (en) 2004-02-29
US6888009B2 (en) 2005-05-03
JP2003513084A (ja) 2003-04-08
AR026063A1 (es) 2002-12-26
CN1391567A (zh) 2003-01-15
CN1187348C (zh) 2005-02-02
US20020165403A1 (en) 2002-11-07
MXPA02004313A (es) 2002-11-07
WO2001032642A1 (en) 2001-05-10
CA2389379A1 (en) 2001-05-10
IT1319251B1 (it) 2003-09-26
CA2389379C (en) 2007-04-10
ITMI20002342A1 (it) 2002-04-27
AU7902400A (en) 2001-05-14

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